USPTO Patents Application 09993647

Requested Patent: EP0233559B1

Title: READILY ABSORBED PHARMACEUTICAL COMPOSITION ;

Abstracted Patent: US5002952 ;
Publication Date: 1991-03-26 ;

Inventor(s):

WATANABE MASAHIRO (JP); YOKOYAMA KAZUMASA (JP); HAGA
TAKAHIRO (JP); KONDO NOBUO (JP); KOYANAGI TORU (JP);
SUGi HIDEO (JP); NAKAJIMA TSUNETAKA (JP); YAMADA
NOBUTOSHI (JP) ;

Applicant(s):

ISHIHARA MINING CHEMICAL CO (JP); GREEN CROSS CORP

(JP);

Application Number: US1 9890385998 19890727 ;

Priority Number(s): J P1 9860026589 19860208 ;

IPC Classification: A61 K3 1/505; A61 K47/00; B01 F3/00 ;

Equivalents: CA1281652, DE3778723D, ES2033701T, JP62185013 ;

ABSTRACT:

A pharmaceutical composition comprising a benzoyl urea compound having
the formula: (I) wherein X is a halogen atom or a nitro group, Y is a
hydrogen atom, a halogen atom, a nitro group or a trifluoromethyi group, Z1
is a halogen atom or a trifluoromethyi group, Z2 is a hydrogen atom or a
halogen atom, and A is a =CH-group or a nitrogen atom, and a nonionic
surfactant.

Europaisches Patentamt
European Patent Office
Office europden des brevets

© Publication number:

0 233 559 B1

EUROPEAN PATENT SPECIFICATION

@ Date of publication of patent specification: 06,05-92 © lntCi. 5 :A6lK 31/17, C07C 275/30,

C07C 275/32, C07D 213/64

© Application number: 87101664.8

© Date of filing: 06.02.87

The file contains technical Information submitted
after the application was filed and not included in
this specification

© Readily absorbable pharmaceutics* composition.

03l

O

in
<n

CO
CM

®

Priority: 08,02.86 JP 26589/86

117-119.

Date of publication of application:

© Proprietor: ISHIHARA SANGYO KAISHA, LTD,

26.08.87 Bulletin 87/35

No. 3-22, Edobori 1-chome

Nishl-ku Osaka(JP)

©

Publication of the grant of the patent:

06.05.92 Bulletin 32/19

Proprietor: THE GREEN CROSS CORPORA-

TION

®

Designated Contracting States:

15-1 f Irnabashi 1-chome Htgashf-ku

ETC: r~r> /"*»0 IT* C3CT

titz Utz. to rn ud 1 1 vi L. on

Osaka(JP)

®

References cited:

© Inventor: Kondo, Nobuo

EP-A- 0 025 363

12-303, Kawanakashinmachi

EP-A-0 1G7 214

Dai to- shi Osaka(JP)

EP-A- 0 178 572

Inventor: Nakajima, Tsunetaka

EP-A- 0 192 263

1330-61, Gojono-cho

Kashiwara-shi Nara-kert(JP)

KIRK-OTHWIER "Encylopedia of chemical

Inventor: Watanabe, Masahiro

technology", 3rd edition, vot 5, 1980, page 9,

570-22, Okuradanishimizu

aohn Wiley & Sons, New York

Akashi-shi Hyogo-ken(JP)

Inventor: Yokoyama, Kazumasa

KIRK-OTHWIER "Encyclopedia of chemical

7-2-201, Terauchi 2-chome

technology", 3rd Edition, voK 9, 1980, page

Toyonaka-sht Osaka(JP)

465, -John Wiley & Sons, New York;

Die Tablette T Dr. W, A, Riischel, 1966, page

Note: Within nine months from the publication of the mention of the grant of the European patent, any person
® may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition
Q. shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee
UUt has been paid (Art, 99(1) European patent convention).

Rank Xerox (UK) Business Services

(3.08/2. 18/2.0^

BP 0

233 559 B1

Inventor: Haga, Takahiro

84-7, Hiral-cfro

Kusatsu-shl Shfcja-ken(JP)

Inventor: Yamada, Nobutoshi

321-31, Fuke-cho

Moriyama-shi Shiga-ken(JP)

Inventor: Sugi r Hideo

321-31, Fuke-cho

Morlyama-shl Shiga-ken(JP)

Inventor: Koyanagt, Tory

3F~410 t 151-30, Ninomaru-cho, Mukaijima

Fushfmi-ku Kyoto-shi Kyoto(JP)

© Representative: WachtershSuser,, GUnter, Dr.
Tal 29

W-8000 MUnchen 2{DE)

EP 0 233 559 B1

Description

The present invention relates to an antitumour pharmaceutical composition containing a benzoyl urea
compound as the main component. More particularly, the present invention relates to a pharmaceutical
5 composition whereby the absorbability of an antitumour benzoyl urea compound of the formula:

10

wherein X is a halogen atom or a nttro group, Y is a hydrogen atom, a halogen atom, a nitro group or a
15 trifluorornethyl group, is a halogen atom or a trifluorornethyl group, Z2 is a hydrogen atom or a halogen
atom, and A is a = CH~ group or a nitrogen atom, through the gut, is improved.

The benzoyl urea compounds of the formula 1 are known to have excellent antitumour activities
(Japanese Unexamined Patent Publication No. 109721/1982). However, these compounds are hardly soluble
in water, and accordingly their absorbability through e.g. the gut is poor. Therefore, in order to obtain
20 adequate antitumour activities, it is necessary to increase the dose, whereby there is a possible danger of
adverse effects due to the excessive administration.

It is an object of the present invention to provide a pharmaceutical composition whereby the absor-
bability .of the benzoyl urea compound of the formula I through the gut is improved.

The present inventors have studied various additives with an aim to improve the absorbability of the
25 benzoyl urea compound of the formula I through the gut, and have finally found that certain specific
substances, i.e. nonionic surfactants, are capable of improving the absorbability of the benzoyl urea
compound of the formula I through the gut

Thus, the present invention provides a pharmaceutical composition comprising a benzoyl urea com-
pound of the formula (i) and a non-ionic surfactant; characterized in that the benzoyl urea compound of the
3D formula (1) is in the form of fine particles having an average particle size of from 0.2 to 1,0 ixm and the ratio
of said benzoyl urea compound to the nonionic surfactant is within a range of from 1:5 to 70:1 by weight
Now, the present invention will be described in detail with reference to the preferred embodiments.
In the accompanying drawing, Figure 1 is a graph showing the stability of particles of the pharmaceuti-
cal composition of the present invention.
36 in this specification, the halogen atom is preferably a chlorine atom or a bromine atom.

40

45

50

55

3

EP 0 233 559 B1

10

75

25

The following compounds may be mentioned as iypicat examples of the benzoyl urea compound of the
formula t

Compound No. 1: (Melting point; 182 - 135°C)

CO ilBCONff— ^ O \— C^3

Compound No. 2s (Melting point: 235 ~ 238°C)

Compound Wo. 3; tMeltinq point: 229 - 231°C)

20 ^\ \— ^ Eft

Br

Compound No. 4; (Meltina point; 207 - 208°C)

\ . N :

oo The benzoyl urea compounds of the formula I are known compounds, and they may be prepared by a
method disclosed In e.g. Japanese Unexamined Patent Publication No. 109721/1982 or by a similar
method.

There is no particular restriction as to the nonionic surfactant to be used in the present invention. Any
nonionic surfactant may be employed so long as it Is useful as an additive for pharmaceuticals. Its HLB

35 value (Hydrophile-Upophile Balance) is preferably at least 3. Specific Examples of such nonionic surfactants
include pofyoxyethylene hardened caster oil 20, polyoxyethyiene hardened caster oil 40, polyoxyethyiene
hardened caster oil 60, polyoxyethyiene hardened caster oil 100, polysorbate 60, poiysorbate 65, polysor*
bate 80 t polyoxyethyiene polyoxypropylene glycol, a sucrose fatty acid ester, a glycerol fatty acid ester, a
sorbitan fatty acid ester, a propylene fatty acid ester, a polyoxyethyiene sorbitan fatty acid ester, a

40 polyoxyethyiene sorbitol fatty acid ester, a polyoxyethyiene glycerol fatty acid ester, and a polyethylene
glycol fatty acid ester.

In the present invention, the ratio of the benzoyl urea compound of the formula 1 to the nonionic
surfactant is usually within a range of from 1:5 to 70:1 by weight.

The pharmaceutical composition of the present invention is preferably in the form of fine particles
45 having an average particle size of from 0.2 to 1.0 M>m.

The pharmaceutical composition of the present invention is preferably the one obtained by pulverizing
the benzoyl urea compound of the formula I in an aqueous solution containing the nonionic surfactant,
whereby the composition having the above-mentioned particle size will be prepared. In such a case, the
nonionic surfactant serves as a dispersant The pulverization is preferably conducted by wet pulverization,
so The wet pulverization is a method wherein the material to be pulverized is rotated or snaked together with
beads {particularly glass beads) in a solution containing the dispersant- A machine such as a Dyno-Mile
{KDL-model, manufactured by Dyno-Mile Company) may be employed for this purpose. The concentration
of the benzoyl urea compound of the formula I in the aqueous solution during the pulverization, is from 1 to
70 w/v%, preferably from 20 to 50 w/v%. Particularly when the pulverization is conducted in a wet
55 pulverization system by using the Dyne-mil l T the concentration of the benzoyl urea compound of the formula
I in the aqueous solution is preferably within the above range, The concentration of the nonionic surfactant
as the dispersant is usually from 1 to 30 w/v%, preferably from 2 to 20 w/v%. The glass beads employed
usually have a size of from 0.1 to 1.5 mm in diameter, preferably from 0.25 to 0,5 mm in diameter. The

4

EP 0 233 559 B1

pulverisation time is usually from 5 minutes to 1 hour. After the completion of the wet pulverization, glass
beads will be removed by sieving, and if necessary additives such as a sweetening agent or a perfume may
be added thereto. The composition is then subjected to autoclave sterilization or to filtration for the removal
of bacteria, to obtain a liquid composition.

s The composition of the present invention can be formulated into pharmaceutical formulations by

conventional methods, As such pharmaceutical formulations, oral formulations such as powders, fine
particles, granules, capsules, tablets and liquid drugs may be mentioned.

Such formulations may be prepared by removing water from the above-mentioned Hquid composition
by heat drying, freeze drying, centrifugal separation, membrane filtration, etc-, and then following a

io conventional method for formulation by using or without using conventional pharmaceutical additives.

The pharmaceutical composition of the present invention may usually orally be administered to
mammals (e.g. human beings, horses, catties, dogs t mice, rats, etc.). The dose varies depending upon the
diseased condition, the sex, the body weight, the formulation, etc. However, for instance, when the
composition of the present invention is orally administered against human malignant lymphoma or lung

75 cancer, the benzoyl urea compound of the formula I is administered in a daily dose of from 5 to 100 mg/kg
to an adult in one to three times per week.

As will be evident from Test Example 1, with the pharmaceutical composition of the present invention,
the absorption of the benzoyl urea compound of the formula I from the gut is remarkably improved, and as
wBI be shown from Test Example 2, the stability of the particles in a liquid state is good.

20 By using the pharmaceutical composition of the present invention, it is possible to reduce the dose of
the benzoyl urea compound of the formula I and thus to reduce the side effects or the pain to the patient
when it is administered.

Now, the present invention will be described with reference to Examples and Test Examples.

25 TEST EXAMPLE 1 : Absorption from the gut

Compound No. 3 was suspended in each dispersing solvent containing a dispersant as identified below,
so that the concentration will be 4 w/v%, and after an addition of glass beads (1-1.4 mm in diameter) in an
amount of the same volume, subjected to rotary pulverisation by a Dyno-mH! for 45 minutes. As the

30 dispersant, polyoxyethylene hardened caster oil 60 (HCO60, manufactured by Ntkko Chemical K.K.),
poiyoxyethylene (160) polyoxy propylene (30) glycol (F68, manufactured by Asahi Denka Kogyo K.K.), a
decaglyceiin fatty acid ester (Decagly, ester, manufactured by Nikko Chemical po!ysorbate SO (Tween
80, manufactured by Nakarai Kagaku K,K,) and sucrose fatty acid ester (P1570, Sugar ester, manufactured
by Hish&o K.K.) were employed.

36 Each wet pulverized formulation thus obtained was forcibly oraliy administered by an oral sonde to a
group of two Wtster male rats (body weight 200 g) starved for 18 hours {dose: 200 mg/5 ml/kg). Then,
blood {0.3 ml) was periodically sampled with heparin from the jugular vein.

The blood thus obtained was subjected to separation of the plasma and removal of proteins by using
acetonitrite, and then Compound No, 3 was quantitatively analyzed by a high speed liquid chromatography

40 using a reversed phase column (Nova Pak Cis, 5jjl, 3.9 mm in diameter x 150 mm, Nthon Waters), and the
curve of the concentration in btood was prepared.

From the curve of the concentration in blood, the area below the curve was obtained by using a
trapezoid formula and presented as AUC (Area Under the Curve). The respective values were obtained for
all rats, and the average value and the width is shown in Table 1 .

45 AUC is the highest with HCO60, and F68 follows it.

Table 1

Dispersant

AUC (0-24 nr.) (mcg/mLhr)

1 0 w/v% HCO60

30.67±0.2i

1 0 w/v% F68

26J0±0.51

10 w/v% Decagiy .ester

25.16±1.12

1 0 w/v% Tween 80

24,72±0.39

1 0 w/v% Sugar ester

1 7.44±0,21

5

EP 0 233 559 B1

TEST EXAMPLE 2: Stability of particles

Among the wet pulverized formulations prepared in Test Example 1, the one wherein HCO60 was used
as a dispersant, was subjected to a storage test at room temperature to examine the stability of particles in
5 a liquid state. The change with time of the particle size (up to 3 months) is shown in Figure 1. With HCO60\
the Increase in the particle size was little and the particles were stable.

TEST EXAMPLE 3: Antitumour activities

10 The pharmacological effects of the pharmaceutical compositions obtained by the present invention were
studied.

To BDFi mice (male, 20 - 22 g), L-1210 leukemia cells were intraperitoneal ly inoculated in an amount of
1 x 1 0 G ceNs/mouse, One day later and 4 days later, a test drug was orally administered. It was difficult to
administer the drug In the final formulation form. Therefore, in this test, Compound No. 3, and a 1 0 w/v%
75 MCO60 solution were mixed, and pulverized in a wet system to obtain a liquid suspension, and the liquid
suspension was administered to each mouse in an amount of 0.5 ml. Thereafter, the mice were observed
for survival or death.

The activity was evaluated by a survival rate [T/C (%)] as compared with a control group to which a
physiological saline was administered, and T/C values are shown in Table 2.

20

T/C C % ) = Median survival time of test animals , n n

Median survival time of control animals x

25 As the results, the adequate, antitumour activity of Compound No. 3 was distinctly observed when it was
subjected to wet pulverization together with the specific substance prescribed by the present invention and
no substantial antitumour activity was observed when Compound No. 3 was wet pulverized in the absence
of HCO60 even when the compound was administered in the same dose. Namely, this result indicates that
the absorption i.e. the transfer of Compound No. 3 into blood from the gut, is facilitated by the composition

30 of the present invention. On the other hand, the appearance of toxicity (T/C being less than 100%) in a high
dose region indicates that the absorption is great

This test result indicates that the adequate antitumour activity of Compound No, 3 is observed only in
the case of the pharmaceutical composition of the present invention, and the activity is particularly
remarkable in the composition obtained by wet pulverization. In particular, when HCO60 is used as a

35

40

4$

50

55

6

EP 0 233 569 B1

dispersant, the absorption is good over a wide range, thus Indicating the possibility of an ideal drug when
the dinical application is taken into account.

Table 2

Administered

formulation

T/C £%)

HCO60 + Compound
Dose of Compound

No,
No*

3
3

(Wet pulverized

drug)

400

32

200

128

100

224

50

200

A. 3

■i

12.5

128

6.25

92

HCO60 + Compound
Dose of, Compound

No,

No.

3
3

(Mixed drug)
(mq/kg)

400

-1 2 5

200

117

t Compound
Dose of Compound

No*
No.

3
3

(Wet pulverized
(mcf/kg)

drug)

400

109

200

99

HCO

+ 60 alone

107

Physiological saline

C control )

100

EXAMPLE 1

Compound No. 3 (5 g) was suspended In 50 mi of a 10 w/v% HCO60 aqueous solution, and the
suspension was wet pulverized by a Dyno-miH by using 50 g of glass beads (1-1.5 mm in diameter). After
the completion of pulverization > glass beads were removed by sieving, to obtain a wet pulverized drug of
Compound No. 3.

7

EP 0 233 559 B1

The wet pulverized drug thus obtained was sterilised in an autoclave to obtain a liquid drug of a final
form. Here, instead of the sterilization in an autoclave, it is possible to employ filtration to remove bacteria.
If necessary, a sweetening agent, a perfume, etc, may be added,

5 EXAMPLE 2

To 40 mt of the liquid drug obtained in Example 1, 20 g of lactose was added. The mixture was free^ed
with dry ice-methanol, and then subjected to vacuum drying for 24 hours to remove water. The solid thus
obtained was filled in capsules to obtain capsule drugs.

Claims

1. A pharmaceutical composition comprising a benzoyl urea compound having the formula

wherein X is a halogen atom or a nitro group, Y is a hydrogen atom, a halogen atom, a nitro group or a
trifluoromethyl group, Zi is a halogen atom or a trifluoromethyl group, 7,2 is a hydrogen atom or a
halogen atom, and A is a ™CH* group or a nitrogen atom, and a nonionic surfactant; characterized in
as that the benzoyl urea compound of the formula I is in the form of fine particles having an average
particle size of from 0.2 to 1.0 urn and the ratio of said benzoyl urea compound to the nonionic
surfactant is within a range of from 1 :5 to 70:1 by weight.

2, The pharmaceutical composition according to Claim 1, wherein the nonionic surfactant has a
30 hydropNIe-lipophile balance of at least 3.

3, The pharmaceutical composition according to Claim 1 , wherein the nonionic surfactant is selected from
the group consisting of polyoxyethylene hardened caster oil 20, polyoxyethylene hardened caster oil
40, polyoxyethylene hardened caster oil 60, polyoxyethylene hardened caster oil 100, poiysorbate 60,

35 poiysorbate 65, poiysorbate 80, polyoxyethylene poiyoxy propylene glycol, a sucrose fatty acid ester, a
glycerol fatty acid ester, a sorbitan fatty acid ester, a propylene fatty acid ester, a polyoxyethylene
sorbitan fatty acid ester, a polyoxyethylene sorbitol fatty acid ester, a polyoxyethylene glycerol fatty
acid ester, and a polyethylene glycol fatty acid ester.

40 4* The pharmaceutical composition according to Claim 1> wherein the benzoyl urea compound is N-(2-
nitrobenzoyl)™N'-[3"Chloro-4-(5-halogeno-2-pyrimidinyioxy)phenyl]urea.

5- The pharmaceutical composition according to Claim 1, wherein the benzoyl urea compound is N-(2-
nitrobenzoyl)-N 1 -[3-chloro-4-(5-bromo-2-pyrlmidfnyloxy)phenyf]urea.

45

6. The pharmaceutical composition according to Claim 5, wherein the nonionic surfactant is polyox-
yethylene hardened castor oil 60.

7. A method for preparing the pharmaceutical composition according to claim 1, wherein the benzoyl urea
50 compound of formula I is pulverized in an aqueous solution of nonionic surfactant,

S. The method according to claim 7, wherein the composition is prepared by pulverizing the benzoyi urea
compound of the formula I in an aqueous solution containing the nonionic surfactant, and then removing
water from the liquid composition.

6a

8

EF 0 233 559 B1

Revendicatlons

1. Composition pharmaceutique comprenant un compose cle benzoyl uree repr£sente par la formula :

dans laquelle :

™ X represente un atome d'halogene ou un groupe nitro ;

- Y represent© un atome d F hydrogene F un atome d'halogene, un groupe nitro ou un groupe
trifluoromethyte ;

- Zi represente un atome d'hatogene ou un groupe trifiuorom£thyle ;

- Z 2 represente un atome d'hydrogene ou un atome d'halogene ; et

- A represent© un groupe ~ CH- ou un atome d'azote,
et un agent tensio-actif non-ionique ;

caracterisee par le fait que le compose de benzoyl uree de formule (I) se presents sous & forme de
fines particuies ayant une dimension moyenne de particule de 0 T 2 a 1 t 0 Jim et que le rapport dudit
compose de benzoyl uree a t'agent tensio-actif non-ionique se situe dans la plage de 1;5a 70:1 en
poids.

2. Composition pharmaceutique selon la revendication 1, dans laquelle Pagent tensio-actif non-ionique
presente une balance hydrophile-fipophile d'au moins 3.

3. Composition pharmaceutique selon la revendication 1, dans laquelle Pagent tensio-actif non-ionique est
chois* dans le groupe constitue par I'huile de ricin durcie polyoxygthylenee 20, t'huile de ricin durcie
poiyoxyethylenee 40, Thuile de ricin durcie polyoxyethyfenee 60, Thuile de ricin durcie polyoxyetnyle"-
nee 1QG, le polysorbate 60, ie polysorbate 65 T le polysorbate 80, le polyoxyethylene polyoxypropylene
glycol, un ester d'acide gras et de sucrose, un ester d T acide gras et de glycerol, un ester d'acide gras
et de sorbitan, un ester d'acide gras propylenique, un ester d'acide gras et de sorbttan polyoxyethyie-
ne\ un ester d'acide gras et de sorbitol polyoxyethylene, un ester d'acide gras et do glycerol
polyoxyethylene, et un ester d'acide gras et de polyethylene glycol

4. Composition pharmaceutique seion la revendication 1 y dans laquelle le compose" de benzoyl uree est la
N-(nitro-2 ben£oyt)-N'™[chJoro-3 (halogeno-5 pyrimidinyl-2 oxy)»4 phenyl juree.

5. Composition pharmaceutique selon la revendication 1, dans laquelle le compose de benzoyl uree est la
N-(nitro™2 benzoyl)"N4chloro-3 (bromo-5 pyrimidinyI-2 oxy-4 phenyi]uree.

6. Composition pharmaceutique selon la revendication 5, dans laquelle I'agent tensio-actif non-ionique est
Phuile de ricm durcie poiyoxyethy^n^e 60.

7. Proc£d4 de fabrication de la composition pharmaceutique selon la revendication 1, dans lequel le
compose de benzoyE uree de formule (I) est pulverise dans une solution aqueuse d'agent tensio-actif
non-ionique.

& Precede selon la revendication 7, dans lequel \a composition est preparee par pulverisation du
compose de benzoyl uree de formute (I) dans une solution aqueuse contenant t'agent tensio-actif non-
ionique, puis elimination de Teau a partir de la composition liquide.

9

BP 0 233 559 B1

Patentansp ruche

1. Pharmazeutische Zusammensetzung, umfassend eine BenzoylharnstoffVerbindung der Formel

wobei X fur ein Halogenatom oder eine Nitrogruppe steht, Y fUr ein Wasserstoffatom, ein Halogenatom,
sine Nitrogruppe oder erne Trifiuormethylgruppe steht, Zi fur ein Halogenatom oder eine Trifiuorme-
thyigruppe steht, Z 2 fOr ein Wasserstoffatom oder ein Halogenatom steht und A fUr eine ™ CH- -Gruppe
oder ein Stickstoffatom steht, und ein nicrrHonisches Surfaktans, dadurch gekennzeichnei da/? die
Benzoylharnstoffverbindung der Forme! \ in Form feiner Teilchen nYrt einer durchschnittlichen Teiichen-
gr&fie von 0,2 bis 1,0 jxrn voriiegt und das VerhSltnis der Benzoylharnstoffverbindung zu dem nicht-
ionischen Surfaktans in einem Bereich von 1 : 5 bis 70 : 1 , naeh Gewicht, liegt

Z Pharmazeutische Zusammensetzung gemafi Anspruch 1, wobei das nicht-ionische Surfaktans eine
hydrophil-lipophil-Balance von rnindestens 3 hat.

3. Pharmazeutische Zusammensetzung gem§£ Anspruch 1, wobei das nicht-ionische Surfaktans ausge-
wahlt ist aus der Gruppe besiehend aus Polyoxyethylen-gehMrtetem Rhizinusol 20, Polyoxyethylen™
gehartetem Rhizinusdl 40, Polyoxyethylen-geh&rtetem Rhizinus5i 60, Polyoxyethylen-gehSrtetem Rhizi-
nusol 100, Polysorbat 80, Polysorbat 65, Polysorbat 80, Poiyoxyethylenpolyoxypropytengtykol, einem
SucrosefettsSureester, einem Glycerinfettsaureester, einem Sorb&anfettsaureester, einem Propyienfett-
saureester, einem Polyoxyethylensorbitanfettsaureester, einem Polyoxyethylensorbitfettsaureester, ei-
nem Poiyoxyethyiengiycerinfetts&ureester und einem Poiyethylenglykolfettsaureester.

4. Pharmazeutische Zusammensetzung gema# Anspruch 1, wobei die Benzoylharnstoffverbindung N-(2-
Nitrobenzoyi)-N t -[3-chior»4»(5-halogen-2-pyrimtdinyloxy)pheny!Jharnstoff ist,

5. Pharmazeutische Zusammensetzung gernatf Anspruch 1 t wobei die Benzoylharnstoffverbindung N-(2-
Nitrobenzoyl)-N t -[3-chlor"4"(6"brom-2»pyrimidinyioxy)phenyl]hamstoff ist.

6. Pharmazeutische Zusammensetzung gemS/3 Anspruch 5, wobei das nlchNonische Surfactans
Folyoxyethylen-gehSrtetes Rhizinusol 60 ist.

7. Verfahren zur HersteMung der pharmazeutischen Zusammensetzung gerna/J Anspruch 1, wobei die
Benzoylharnstoffverbindung der Forrnet 1 En einer wassrigen Losung von nichHonischem Surfactans
puiverisiert wtrd,

& Verfahren gemS£ Anspruch 7, wobei die Zusammensetzung hergestellt wird, indem man die Benzoyl-
harnstoffverbindung der Formel ( in einer wassrigen Losung, enthaltend das nicht-ionische Surfactans,
puiveristert und anschliefiend Wasser aus der flussigen Zusammensetzung entfernt

10

EF 0 233 559 B1

FIGURE

Stability of particles

6-

N

00

s

3

e

>

5 -

0

)0%HC060

O

Storage period (months)

11